The goals of this project are to detect and accurately describe perimenopausal and midlife-related mood disorders, explore their pathophysiology and response to pharmacological and environmental manipulation, and to document the relationship between reproductive endocrine change and disorders of mood as a way of further investigating the neurobiology of psychiatric illness. Findings to date include: 1) significant improvement in measures of depression severity scores and verbal memory performance (but not libido) after estrogen replacement in women with perimenopausal depression independent of estrogen's salutary effects on vasomotor symptoms; 2) the recurrence of depressive symptoms after the administration of the serotonin agent metergoline but not placebo in seven depressed perimenopausal women who responded to estrogen replacement under placebo-controlled conditions; 3) significant improvement in depression severity scores (but not measures of cognitive function or libido) after DHEA administration in 18 men, but not 18 women, with midlife-related depression; and 4) significant increases in plasma levels of the testosterone metabolite and putative neurosteroid androsterone after DHEA administration in men. Results are pending for studies of the effects of DHEA on the following: plasma androsterone levels (in men and women); plasma and urinary markers of bone metabolism; bone density (DEXA); and vascular motility. In a companion experimental paradigm involving the induction of hypogonadism in men and women with GnRH agonists we have observed the hypogonadal state to be associated with the following: 1) decreased measures of sexual function in both men and women, with a restoration of normal sexual function during gonadal steroid replacement in 20 men with testosterone but not in 17 women with either estradiol or progesterone; 2) no significant effects on measures of cognitive function in either women or men (in contrast to estradiol-related improvement in verbal memory observed in the older perimenopausal women); 3) no significant effects on mood and behavioral symptoms in men (with the exception of libido and hot flushes); 4) elimination of cognition activated regional cerebral blood flow (O15 PET scans) in the dorsolateral prefrontal cortex in women but not men and preliminary evidence of a similar pattern of cognition activated r-CBF employing different cognitive activation paradigms and using 3D PET and FMRI techniques; 5) decreased cerebral spinal fluid (CSF) measures of testosterone (T), dihydro T, and androsterone (relative to T replacement) but no gonadal steroid-related differences in CSF measures of monoamine metabolites in men; and 6) decreased cortisol secretion after exercise stress in women (relative to progesterone replacement) and decreased ACTH secretion after o-CRH in men. Additionally, we have observed sexual dimorphisms during the hypogonadal state (i.e. gender differences that are independent of the presence of gonadal steroids) in several measures: m-CPP stimulated growth hormone secretion (increased in women); spatial ability (increased in men), and ACTH and cortisol response to exercise stress (increased in men). Finally, we have initiated collaborative investigations with the NICHD to examine the effects of T replacement on mood and behavior in women with Turner's Syndrome and in women with premature ovarian failure.